Glaucoma
Glaucoma, which is the leading cause of blindness in the United States, is a group of diseases characterized by progressive atrophy of the optic nerve head leading to visual field loss, and, ultimately, blindness. Glaucoma is generally associated with elevated intraocular pressure, which is an important risk factor for visual field loss because it causes further damage to optic nerve fibers.
There are several types of glaucoma, including open and closed angle glaucoma, all involve the abnormal increase in intraocular pressure, primarily by obstruction of the outflow of aqueous humor from the eye, or, less frequently, by over production of aqueous humor within the eye. The most prevalent type is primary open angle glaucoma in which the aqueous humor has free access to the irridocorneal angle, but aqueous humor drainage is impaired. In contrast, in closed angle glaucoma, the irridocorneal angle is closed by the peripheral iris. The angle block can usually be corrected by surgery. Less prevalent types of glaucoma include secondary glaucomas related to inflammation, trauma and hemorrhage. Glaucoma in its various forms is widely described in the literature: see, e.g., Leibrandt, ed. (1982) Professional Guide to Diseases, pp. 1203-1206 and Andreoli et al., eds. (1986) Cecil: Essentials of Medicine, pp. 690-691.
Therapeutic treatment of glaucoma is directed at reducing intraocular pressure. Because intraocular pressure is controlled by aqueous humor dynamics, an understanding of the production and removal of aqueous humor from the eyeball provides insights into the causes of increased ocular pressure associated with glaucoma. Aqueous humor is similar in electrolyte composition to plasma, but has a lower protein content. The aqueous humor keeps the eyeball inflated, supplies the nutritional needs of the vascular lens and cornea and washes away metabolites and toxic substances within the eye. The bulk of aqueous humor formation is the product of active cellular secretion by nonpigmented epithelial cells of the ciliary process from the active transport of solute, probably sodium, followed by the osmotic flow of water from the plasma. The nonpigmented epithelial cells of the ciliary process are connected at their apical cell membranes by tight junctions. These cells and the nonfenestrated iris vessels form the blood/aqueous barrier through which blood-borne large molecules, including proteins, do not pass.
Intraocular pressure is a function of the difference between the rate at which aqueous humor enters and leaves eye. Aqueous humor enters the posterior chamber by three means: 1) active secretion by nonpigmented epithelial cells of the ciliary process; 2) ultrafiltration of blood plasma; and 3) diffusion. Newly formed aqueous humor flows from the posterial chamber around the lens and through the pupil into the anterior chamber; aqueous humor leaves the eye by passive bulk flow at the irridocorneal angle and uveoscleral outflow. Any change in 1), 2) or 3) will disturb aqueous humor dynamics and likely alter intraocular pressure.
Treatments for Glaucoma
Most treatments for glaucoma focus on reducing intraocular pressure. Treatment has involved administration of beta-blockers such as timolol to decrease aqueous humor production, epinephrine to lower intraocular pressure or diuretics such as acetazolamide to reduce aqueous production, or administration of miotic eyedrops such as pilocarpine to facilitate the outflow of aqueous humor. Acute forms of glaucoma may require peripheral iridectomy surgery to relieve pressure where drug therapy is ineffective and the patient's vision is at immediate risk. Other forms of treatment have included physical or thermal destruction ("cyclo-destruction") of the ciliary body of the eye, commonly by surgery or application of a laser beam, cryogenic fluid or high frequency ultrasound. Each of these methods of destruction is costly and unduly inversive.
There are many problems, however, in effectively treating glaucoma and with long term medicinal or surgical therapies. One problem is the difficulty in devising means to generate pharmacologically effective intraocular concentrations and to prevent extraocular side effects elicited by systemic administration. Many drugs are administered topically or locally. The amount of a drug that gets into the eye is, however, only a small percentage of the topically applied dose because the tissues of the eye are protected from such substances by numerous mechanisms, including tear turnover, blinking, conjunctival absorption into systemic circulation, and a highly selective corneal barrier.
Also, there is a risk for developing an intolerance to medical therapy or laser therapy, so that a filtration operation for control of intraocular pressure may become necessary. Present surgical techniques to lower intraocular pressure, when medication fails to decrease fluid flow into the eye or to increase fluid outflow, include procedures that permit fluid to drain from within the eye to extraocular sites by creating a fluid passageway between the anterior chamber of the eye and the potential supra-scleral/sub-Tenon's space, or, alternatively, into or through the Canal of Schlemm (see, e.g., U.S. Pat. No. 4,846,172). The most common operations for glaucoma are glaucoma filtering operations, particularly trabeculectomy. These operations involve creation of a fistula between the subconjunctival space and the anterior chamber. This fistula can be made by creating a hole at the limbus by either cutting out a portion of the limbal tissues with either a scalpel blade or by burning with a cautery through the subconjunctival space into the anterior clamber. Fluid then filters through the fistula and is either gradually absorbed by vessels within the conjunctiva or gradually filters through the conjunctival tissues to be extruded externally with the tears. In order for the surgery to be effective, the fistula must remain substantially unobstructed. These drainage or filtering procedures, however, often fail by virtue of closure of the passageway resulting from the healing of the very wound created for gaining access to the surgical site. Failures most frequently result from scarring at the site of the incisions in the conjunctiva and the tenon's capsule. The surgery fails immediately in at least 15% of patients, and long term in a much higher percentage. Presently, this consequence of trabeculectomy, closure of the passageway, is treated with 5-fluorouracil and mitomycin C, which apparently prevent closure by inhibiting cellular proliferation. These drugs, however, are highly toxic and have undesirable side effects, including scleral melting.
In view of the limited number of treatment options, there is, therefore, a need to develop more effective treatments for glaucoma. Therefore, it is an object herein to provide compositions and methods for treatment of glaucoma.